Anti-apoptotic Bcl-2 family protein members are associated with a number of diseases and thus are under investigation as potential therapeutic drug targets. These important targets for interventional therapy include, for example, the Bcl-2 family of proteins Bcl-2, Bcl-XL and Bcl-w. Recently inhibitors of Bcl-2 family members have been reported in the literature, see, for example, WO 2005/049594, Oltersdorf, et. al. Nature 2005, 435, 677-681, U.S. Pat. Nos. 6,720,338 and 7,030,115. While this art teaches inhibitors having high binding to the target protein, this is only one of many parameters that must be considered as a compound is investigated for further or continued drug development. As part of this development, it is highly desirable to produce compounds that are efficacious in animal models of cancer after oral administration. To achieve this oral efficacy, it is well known in the art that a compound must not only display potent activity against a tumor type or cell line under investigation, but must also achieve acceptable levels of systemic exposure after oral administration. A typical measure of cellular activity is the concentration eliciting 50% cellular effect (EC50). A typical measure of systemic exposure is the area under the curve resulting from graphing the plasma compound concentration after oral administration vs. time (AUC). The ratio between these parameters (AUC/EC50) is well known in the art to constitute a useful pharmacodynamic parameter to predict oral efficacy.
The inventors have discovered that while compounds taught in the art may have either potent cellular efficacies or high systemic exposures after oral administration to animals, they do not possess both properties. This results in a low AUC/EC50 ratio and renders these compounds not orally efficacious. This invention is directed to a series of haloalkylsulonylaryl analogs that demonstrate enhanced and unexpected properties with respect to cellular efficacy and systemic exposure after oral administration in animals. Specifically, compounds of this invention maintain potent cellular efficacy while exhibiting suitable systemic exposure after oral administration to animals. This results in AUC/EC50 ratios significantly higher than that of the compounds taught in the art.